1.1. Detailed interview

Ideally the medical history should cover:

• History of bacterial infections (especially urinary tract infection)
• History of fungal infections
• Risk of latent or active tuberculosis:
  • date of the last BCG vaccination
  • potential contact with patients having tuberculosis
  • country of origin, or prolonged stay in an area endemic for tuberculosis
  • history of treatment for latent or active tuberculosis
• History of varicella-zoster virus infection (chickenpox/ shingles)
• History of herpes simplex virus infection
• Immunisation status for hepatitis B
• History of travel and/or living in tropical area or countries with endemic infections
• Future plans to travel abroad to endemic areas.

1.2. Physical examination

General physical examination best includes a search for features that often pass without comment, because they are of minor significance in people who are generally healthy, but which may have substantial implications when immunosuppressed:

• Systemic or local signs of active infection (including gingivitis, oral or vaginal candidiasis, or intertrigo as features of fungal infection)
• Cervical smear.

1.3. Laboratory tests

Many opportunistic infections are preventable and the potential for severe infection during immunosuppression can be ameliorated if thought is given to identifying risks before starting immunomodulator therapy. Ideally, baseline tests, potentially performed at diagnosis, should include:

• Neutrophil and lymphocyte cell count
• C-reactive protein
• Urine analysis in patients with prior history of UTI or urinary symptoms
• Varicella zoster virus (VZV) serology in patients without a reliable h/o of varicella immunisation
• Hepatitis B virus serology
• Human immunodeficiency virus (HIV) serology after appropriate counselling
• Eosinophil cell count, stool examination and strongyloidiasis serology (for returning travellers).

1.4. Screening for tuberculosis

Screening for tuberculosis should be considered before using high dose corticosteroids or immunomodulators other than anti-TNF therapy, although it is considered mandatory for the latter group.

1. Clinical context of risk (gathered from a detailed history, above)
2. Chest radiograph within 3 months of starting therapy
3. Interferon gamma release assay.

If any of the above 1, 2 or 3 is positive, the patient should be referred for assessment  to a specialist with an interest in TB. If IGRA is indeterminate or equivocal, it could be repeated after 2-3 weeks and if still indeterminate or equivocal- the patient should be referred for assessment to a specialist with an interest in Tb

1.5. Vaccination

Vaccines are best given before introduction of immunomodulators therapy. Consideration could reasonably be given to a vaccination programme at diagnosis of IBD, since around 80% of patients will be treated with corticosteroids, 40% with thiopurines and 20% with anti-TNF therapy.

As in the general population, the immunisation status of patients with inflammatory bowel disease should be checked and vaccination considered for routinely administered vaccines: tetanus, diphtheria, poliomyelitis. In addition, every patient with IBD should be considered for the five following vaccines, ideally at diagnosis for the reasons above:

• VZV varicella vaccine (if there is no medical history of chickenpox, shingles, or VZV vaccination and VZV serology is negative
• Human papilloma virus
• Influenza (trivalent inactivated vaccine) once a year
• Pneumococcal polysaccharide vaccine
• Hepatitis B vaccine in all HBV seronegative patients.

Vaccines for patients on immunomodulators travelling in developing countries or frequently travelling around the world should be discussed with an appropriate specialist.

1.6 Other precautions

• Exclude Pregnancy
• Contraception during and 5 months (for Humira) after stopping the treatment- if pregnant need to report to Manufacturer’s registry.
• Not to breast feed (breast feeding is a contraindication for biologics)
• Monitor FBC/LFT/Urea electrolytes every week for a month, then twice monthly and then monthly
• Previous history of neurological disease (caution should be exercised when using biologics for patients with h/o CNS demyelinating disorders)
• Previous history of cancer
• H/o Cardiac failure (biologics are contraindicated in moderate to severe heart failure, exercise caution with mild heart failure)

Ref:

http://www.ecco-ibd.eu/images/stories/docs/guidelines/oi_eccoconsensus.pdf

Anti-TNF therapy increases the risk of TB infection. When TB occurs in patients on anti-TNF therapy, it is more commonly atypical (extrapulmonary in >50%, disseminated in 25% of cases), making the diagnosis more difficult. Mortality in patients with TB during anti-TNF therapy has been reported to be up to 13%.

Five to ten per cent of Tuberculin skin test (TST) positive individuals will progress from this clinically asymptomatic state (here termed latent TB infection (LTBI) to active disease. The use of anti-TNF? agents increases the risk of LTBI progressing to active TB by approximately fivefold. This is often rapid and aggressive, occurring at a median of 12 weeks from anti-TNF? initiation in the earliest reports. Thus, the onset of new respiratory symptoms, particularly within 3 months of commencing anti-TNF treatment, should be investigated promptly

Thus, all patients should be screened for latent TB before initiating anti-TNF treatment.

How to diagnose latent tuberculosis?

All patients should have:

1. Careful history: Previous h/o TB or TB treatment
2. CXR: within 3/12 of starting biologics. An abnormal chest radiograph suggestive of old TB (calcification >5 mm, pleural thickening, or linear opacities) should also be considered suggestive of latent TB even if other criteria are absent.
3. TB IFN? release assays (IGRA)

If any of the above 1, 2 or 3 is positive, the patient should be referred for assessment to a specialist with an interest in TB. If IGRA is indeterminate or equivocal, it could be repeated after 2-3 weeks and if still indeterminate or equivocal- the patient should be referred for assessment to a specialist with an interest in Tb

Discuss the treatment of latent TB?

There are two potential chemoprophylaxis regimens: isoniazid for 6 months (6H) or rifampicin plus isoniazid for 3 months (3RH).

It should be noted that no chemoprophylaxis regimen is wholly effective; protective efficacies of 60% have been reported for 6H and of 50% for 3RH. If patients who have had chemoprophylaxis develop symptoms suggestive of clinical TB, they should be promptly and appropriately investigated.

Discuss monitoring with latent TB treatment?

Isoniazid-related hepatotoxicity occurs in approximately 0.15% of patients. It may occasionally be severe and life threatening.  Minor transaminase elevations (3-fold) are common (10–20%) during isoniazid therapy and of no consequence.

Most advise monitoring liver function at intervals, with cessation or alteration of therapy if the transaminases exceed >3-fold elevation associated with hepatitis symptoms or jaundice, or >5-fold in the absence of symptoms.

If a patient needs to start Latent TB treatment, when can they safely start anti-TNF? agents?

Patients with active TB should receive a minimum of 2 months full chemotherapy directed by a specialist in TB before starting anti-TNF-a treatment.

Discuss the disadvantages of TST?

• Diagnosis of latent TB by TST may be distorted by prior BCG vaccination, because vaccinated individuals may become positive reactors to purified protein derivate (PPD). This distortion is almost insignificant in adults >30 years of age, irrespective of age at vaccination or re-vaccination.
• TST may also be negative in patients on steroids (>20mg/day) for >1 month, or thiopurines or methotrexate for >3 months. The TST cannot adequately be interpreted if corticosteroids are not discontinued for >1 month and immuno modulators for >3 months.
• A false negative TST may also occur during active IBD without immuno suppression.

Thus, NICE recommends an interferon-gamma test in immunosuppressed patients and in BCG vaccinated people

Discuss IFN? release assays (IGRAs) tests for TB?

Principle: T cells of individuals who have been exposed to TB (and hence its antigens) will produce IFN? when they are re-challenged with mycobacterial antigens contained within the test kit.

Mycobacterial antigens used for the test: ‘early secretion antigen target 6? (ESAT-6), ‘culture filtrate protein 10? (CFP-10) and tb7.7. These antigens are not present in BCG, and are found in only a few species of environmental mycobacteria.

Tests available: There are currently three interferon-gamma immunological tests commercially available: QuantiFERON-TB Gold, QuantiFERON-TB Gold In tube and T-SPOT.TB.

QuantiFERON-TB Gold measures the release of interferon-gamma in whole blood in response to stimulation by ESAT-6 and CFP-10. The In tube version measures ESAT-6, CFP-10 and tb7.7.

T SPOT-TB measures IFN? production (using ESAT-6 and CFP-10 antigens) from a fixed number of blood mononuclear cells via an ex vivo overnight enzyme linked immunospot (ELISPOT) assay.

Results: Each time that a test is run on a blood sample, a negative control (which contains no stimulating antigen) and a positive control (with mitogen) are also tested against the blood sample. Indeterminate results occur when either the negative control records a positive result, (i.e., the blood sample’s T cells release IFN? without specific stimulation) or the mitogen does not stimulate the cells as expected (and no IFN? is produced). Indeterminate results are particularly common in the populations where a clear-cut result would be most helpful, such as the immunosuppressed, patients in an intensive care unit, children and older adults.

Advantages of IGRA tests over TST:

Results are usually available within 24–48 h

More specific than the TST in BCG-vaccinated populations

No follow-up visit is required

More sensitive and specific than TST

References

1. British Thoracic Society Guidelines (hyperlink to

http://www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/Tuberculosis/Guidelines/antitnf.pdf

2. Greveson K et al . Interferon ?-release assays for detecting latent tuberculosis infection in patients scheduled for anti-TNF? therapy. Frontline Gastroenterology 2011;2:26–31. doi:10.1136/fg.2009.000356

3. NICE guidance 2011 (link it to http://www.nice.org.uk/nicemedia/live/13422/53638/53638.pdf

When?

• Moderately to severely active Crohn’s disease that is refractory to conventional therapy.
• Fistulising Crohn’s disease that is refractory to conventional therapy

Clinical trials have demonstrated significant utility of infliximab for induction of remission in moderately active, steroid refractory Crohn’s disease, improvement in quality of life, and maintenance of remission in these patients for up to 54 weeks after initial infusion.

How?

2 strategies

• Scheduled maintenance- Dose 5mg/kg. Induction doses at 0,2 and 6 weeks and then retreatment of patients who respond to initial therapy every four- to eight-week interval at 5 mg/kg  depending upon how quickly relapse of the Crohn’s disease symptoms occurs.
• Episodic use- on demand retreatment with 5 mg/kg after a single inductive infusion of infliximab. Inductive infusion is at 0, 2 and 6 weeks for fistulising Crohn’s disease and then on demand retreatment.

Discuss episodic treatment? (NICE recommends episodic treatment)

• Safety and cost are important aspects of all drug usage.  Toxicity is not substantially enhanced and infusion reactions are not decreased by regularly scheduled infusions.
• Drug costs tend to decrease with time and competition and thus should not be used as a major reason for opting for an episodic regime. Further considering the costs of surgery and hospitalisations, a maintenance regime of infliximab is cost effective.
• In ACCENT I study, the authors stress the clinical superiority of the scheduled maintenance treatment groups over the episodic strategy, with significant advantages in remission and response rates, quality of life, mucosal healing, Crohn’s disease related hospitalizations, and intra-abdominal surgery. However, regularly scheduled administration of the FDA-approved dose of 5 mg/kg infliximab was significantly better than episodic infusion in only 2 parameters (hospitalization, 23% vs. 38%; P =0.047; intra-abdominal surgeries, 3% vs. 7%; P =0.04).
• Remission and response are the most widely accepted outcome measurements for Crohn’s disease clinical trials. ACCENT I-  only a minority of patients (44%) in the 5-mg/kg regularly scheduled group completed the study as designed; 26% discontinued treatment without crossover and 30% were crossed over to 10 mg/kg “rescue” therapy. Therefore, an alternative interpretation of these results is that on-demand retreatment with 5 mg/kg after a single inductive infusion of infliximab is comparable to the more expensive strategy of 3 inductive infusions followed by scheduled treatments every 8 weeks.
• Certainly, a patient with luminal Crohn’s disease who requires infliximab treatment and who is not yet on immunosuppressant drugs can be induced with a single infliximab infusion after beginning maintenance 6MP, azathioprine, or methotrexate, thereby reserving regularly scheduled infliximab infusions for those patients failing optimal immunosuppressant maintenance treatment.

Discuss management strategy of patients who initially respond but then lose their response?

Antibodies to infliximab reduce infliximab blood levels and causes loss of response. This can be overcome by 4 different strategies;

• decrease the intervals between re infusions to 7, 6, 5, or 4 week intervals
• increase the infliximab dose to 10 mg/kg
• Both
• Switch to adalimumab

Discuss efficacy of infliximab treatment?

Adalimumab

Discuss dosing?

The approved induction dosing of adalimumab in Crohn’s disease is 160 mg given subcutaneously initially at week zero, 80 mg at week two, followed by a maintenance dose of 40 mg every other week beginning at week four. The drug is available in a single-use prefilled pen (HUMIRA Pen)

Discuss the efficacy?

Patients generally respond within the first week. Responses were maximal by three doses in the CLASSIC and CHARM studies. Patients who do not respond within this interval should not continue adalimumab.

Efficacy similar to Infliximab

Discuss the indications?

• Same as Infliximab
• Adalimumab can be used in patients who had lost response to or are intolerant of infliximab. Used as such in GAIN study, adalimumab was more effective than placebo at achieving clinical remission (21 versus 7 percent) and response (38 versus 25 percent)

Dosing of Adalimumab:

Starting Dose:

On day 1* 4 (four 40 mg) injections of HUMIRA. (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days)
On day 15 2 (two 40 mg) injections of HUMIRA.

Continuing Dose:

On day 29 1 (one 40 mg) injection of HUMIRA.
After day 29 regular scheduled dose of one Pen (40 mg) every other week.

How to use the pen:

http://www.myhumira.com/Administering/Instructions.aspx?p=pen

How to use the syringe:

http://www.myhumira.com/Administering/Instructions.aspx?p=syringe

Patient information about Adalimumab: from NACC website

http://www.rxabbott.com/pdf/humira_medguide.pdf

Breast feeding and Adalimumab?

As the long-term effects of adalimumab on a child’s developing immune system are still not known, it is recommended that patient should not breast-feed during treatment or for six months after last dose.

Does adalimumab affect pregnancy?

There have been several reports of successful pregnancies in women with Crohn’s on adalimumab before conception or during pregnancy. Because the drug is relatively new the clinical evidence is limited therefore, the manufacturers recommend that woman of childbearing age should use adequate contraception to prevent pregnancy and continue to use it for at least 5 months after stopping taking adalimumab.

However, in many cases the risks of active Crohn’s disease outweigh the risks of the drug, even during pregnancy. In severe Crohn’s disease when patient  do not want to wait before trying for a baby the doctor and the patient together will have  to weigh up the risk of stopping against the benefits of continuing with treatment.

If the patient becomes pregnant while using adalimumab there may be reasons to continue throughout the first 6 months of pregnancy. In the last 3 months of pregnancy adalimumab should only be used with caution as it will cross the placenta and might affect the immune system of baby.

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Chromoendoscopy technique uses a locally staining agent applied onto the
mucous membrane during the endoscopic examination to  improve tissue localization, characterization, or diagnosis during endoscopy. The method is cheap; the colouring agents are widely accessible and non-toxic.
The technique for staining is simple and easy to learn. The endoscope and catheter tip is directed toward the mucosa and a combination of rotational clockwise-counter clockwise movements is used to spray the mucosa through a catheter while simultaneously withdrawing the endoscope tip. Buscopan may help to minimize contractility and thereby facilitate staining.
The impact of chromoendoscopy on clinical outcomes relative to standard endoscopic and histologic methods has not yet been established in large controlled trials.
Currently used staining agents

1. Indigo carmine-
2. It pools in crevices between epithelial cells thereby highlighting small or flat lesions and defining irregularities in mucosal architecture.
3. It is used to
4. To assist in detection of dysplastic changes in patients with ulcerative colitis undergoing surveillance colonoscopy.
5. To assist in detection of adenomas in patients with hereditary nonpolyposis colorectal cancer.
6. To diagnose small gastric cancers
7. Methylene blue
8. Methylene blue is absorbed by actively absorbing tissue like small and large intestinal epithelium, staining them blue. It does not stain nonabsorptive epithelium like squamous or gastric epithelium.
9. The most extensive experience with methylene blue has been in the evaluation of Barrett’s oesophagus. Barrett’s oesophagus stains diffusely with methylene blue because of the specialised columnar epithelium. Dysplasia/carcinoma is associated with focal areas of decreased stain intensity and/or increased stain heterogeneity due to the differential absorption of methylene blue dye into dysplastic cells that have varying degrees of goblet cell loss. Thus, abnormal methylene blue staining is helpful in delineating dysplastic or malignant areas for diagnosis and endoscopic therapy, if needed.

Recently concerns has been raised regarding the potential to induce oxidative damage to DNA (and hence accelerate carcinogenesis) in tissues exposed to methylene plus white light (such as during endoscopy).  However, this theoretical risk for increasing neoplastic transformation has not been proven by clinical studies.